Muskarinski acetilholinski receptor M₂

Muskarinski acetilholinski receptor M2‎‎
Identifikatori
Simboli	CHRM2; FLJ43243; HM2; MGC120006; MGC120007
Vanjski ID	OMIM: 118493 MGI: 88397 HomoloGene: 20190 IUPHAR: M2 GeneCards: CHRM2 Gene
Ontologija gena
Molekularna funkcija	• aktivnost receptora; • aktivnost G-protein spregnutog receptora; • aktivnost muskarinskog acetilholinskog receptora; • proteinsko vezivanje;
Celularna komponenta	• ćelijska membrana; • integralno sa ćelijskom membranom; • sinapse; • postsinaptička membrana;
Biološki proces	• signalni put G-protein spregnutog receptora; • G-proteinska signalizacija, spregnuta sa cikličnim nukleotidnim drugim glasnikom; • G-proteinska signalizacija, spregnuta sa cAMP nucleotidnim drugim glasnikom; • aktivacija aktivnosti fosfolipaze C signalnim putem muskarinskog acetilholinskog receptora; • razvoj nervnog sistema; • regulacija kontrakcija srca; • respons na virus;
Ortolozi

edit

Muskarinski acetilholinski receptor M₂ (holinergički receptor, muskarinski 2) je muskarinski acetilholinski receptor.

Funkcija

Srce

M2 muskarinski receptori su locirani u srcu, gde usporavaju brzinu srca do normalnog sinusnog ritma nakon stimulatornog dejstva simpatetičkog nervnog sistema, putem usporavanja brzine depolarizacije. Oni takođe redukuju kontraktilne sile atrijalnog srčanog mišića, i umanjuju provodnu brzinu atrioventrikularnog čvora (AV čvor). Oni nemaju efekta na kontrakcione sile ventrikularnog mišića.

IQ

Jedna danska porodična studija iz 2006 je utvrdila da postoji "veoma značajna veze" između CHRM2 gena i inteligencije. Ova studija je koristila uzorak od 667 osoba iz 304 porodice.^[1] Slična veza je nezavisno nađena u studiji blizanaca i porodica u Minesoti.^[2] Međutim, kasniji pokušaji iz 2009. da se potvrde ove tvrdnje je bili neuspešni.^[3]

Mehanizam

M2 muskarinski receptori deluju putem G_i tipa receptora, koji uzrokuju smanjenje cAMP koncentracije u ćeliji, generalno dovodeći do inhibitornih efekata.

Oni takođe moduliraju muskarinske kalijumove kanale.^[4]^[5] U srcu, oni doprinose smanjenju brzine rada srca.

Gen

Muskarinski acetilholinski receptor M2 je kodiran genom CHRM2.^[6] Višestruke alternativno splajsovane transkriptne varijante ovog gene au nađene.^[6]

Ligandi

Nekoliko visoko selektivnih M2 agonista je trenutno dostupno. Brojni neselektivni agonisti i antagonisti su poznati.

Agonisti

Betanehol (neselektivni muskarinski agonist)
(2S,2'R,3'S,5'R)-1-methil-2-(2-methil-1,3-oksatiolan-5-il)pirolidin 3-sulfokside metil jodid (selektivni parcijalni M2 agonist)^[7]

Antagonisti

Dimetinden - N,N-Dimetil-3-[(1S)-1-(2-piridinil)etil]-1H-inden-2-etanamin, CAS# 121367-05-3, mešoviti M2 / histamin H1 antagonist
Otenzepad - 11-([2-[(Dietilamino)metil]-1-piperidinil]acetil)-5,11-dihidro-6H-pirido[2,3-b][1,4]benzodiazepin-6-on, CAS# 102394-31-0
AQRA-741 - 11-([4-[4-(Dietilamino)butil]-1-piperidinil]acetil)-5,11-dihidro-6H-pirido[2,3-b][1,4]benzodiazepin-6-on, CAS# 123548-16-3
AFDX-384 (mešoviti M2/M4 antagonist) - N-[2-[2-[(Dipropilamino)metil]-1-piperidinil]etil]-5,6-dihidro-6-okso-11H-pirido[2,3-b][1,4]benzodiazepin-11-karboksamid, CAS# 118290-27-0

Povezano

Muskarinski acetilholinski receptor

Reference

↑ Gosso MF, van Belzen M, de Geus EJ, et al. (2006). „Association between the CHRM2 gene and intelligence in a sample of 304 Dutch families”. Genes, Brain and Behavior 5 (8 pages=577–584). DOI:10.1111/j.1601-183X.2006.00211.x. PMID 17081262.
↑ Dick DM, Aliev F, Kramer J, et al. (2007). „Association of CHRM2 with IQ: converging evidence for a gene influencing intelligence”. Behav. Genet. 37 (2): 265–272. DOI:10.1007/s10519-006-9131-2. PMID 17160701.
↑ Lind PA, Luciano M, Horan MA, et al. (September 2009). „No association between Cholinergic Muscarinic Receptor 2 (CHRM2) genetic variation and cognitive abilities in three independent samples”. Behav. Genet. 39 (5): 513–23. DOI:10.1007/s10519-009-9274-z. PMID 19418213.
↑ Rang, H. P. (2003). Pharmacology. Edinburgh: Churchill Livingstone. ISBN 0-443-07145-4.
↑ Boron, W. F and Boulpaep, E. L. (2005). Medical Physiology. Philadelphia: Elsevier Saunders. str. 387. ISBN 1-4160-2328-3.
↑ ^6,0 ^6,1 „Entrez Gene: CHRM2 cholinergic receptor, muscarinic 2”.
↑ Scapecchi S, Matucci R, Bellucci C, Buccioni M, Dei S, Guandalini L, Martelli C, Manetti D, Martini E, Marucci G, Nesi M, Romanelli MN, Teodori E, Gualtieri F (March 2006). „Highly chiral muscarinic ligands: the discovery of (2S,2'R,3'S,5'R)-1-methyl-2-(2-methyl-1,3-oxathiolan-5-yl)pyrrolidine 3-sulfoxide methyl iodide, a potent, functionally selective, M2 partial agonist”. J. Med. Chem. 49 (6): 1925–31. DOI:10.1021/jm0510878. PMID 16539379.

Literatura

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van Koppen CJ, Nathanson NM (1991). „Site-directed mutagenesis of the m2 muscarinic acetylcholine receptor. Analysis of the role of N-glycosylation in receptor expression and function.”. J. Biol. Chem. 265 (34): 20887–92. PMID 2249995.
Ashkenazi A, Ramachandran J, Capon DJ (1989). „Acetylcholine analogue stimulates DNA synthesis in brain-derived cells via specific muscarinic receptor subtypes.”. Nature 340 (6229): 146–50. DOI:10.1038/340146a0. PMID 2739737.
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Haga K, Kameyama K, Haga T, et al. (1996). „Phosphorylation of human m1 muscarinic acetylcholine receptors by G protein-coupled receptor kinase 2 and protein kinase C.”. J. Biol. Chem. 271 (5): 2776–82. DOI:10.1074/jbc.271.5.2776. PMID 8576254.
Kostenis E, Conklin BR, Wess J (1997). „Molecular basis of receptor/G protein coupling selectivity studied by coexpression of wild type and mutant m2 muscarinic receptors with mutant G alpha(q) subunits.”. Biochemistry 36 (6): 1487–95. DOI:10.1021/bi962554d. PMID 9063897.
Smiley JF, Levey AI, Mesulam MM (1998). „Infracortical interstitial cells concurrently expressing m2-muscarinic receptors, acetylcholinesterase and nicotinamide adenine dinucleotide phosphate-diaphorase in the human and monkey cerebral cortex.”. Neuroscience 84 (3): 755–69. DOI:10.1016/S0306-4522(97)00524-1. PMID 9579781.
von der Kammer H, Mayhaus M, Albrecht C, et al. (1998). „Muscarinic acetylcholine receptors activate expression of the EGR gene family of transcription factors.”. J. Biol. Chem. 273 (23): 14538–44. DOI:10.1074/jbc.273.23.14538. PMID 9603968.
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Retondaro FC, Dos Santos Costa PC, Pedrosa RC, Kurtenbach E (1999). „Presence of antibodies against the third intracellular loop of the m2 muscarinic receptor in the sera of chronic chagasic patients.”. FASEB J. 13 (14): 2015–20. PMID 10544184.
Waid DK, Chell M, El-Fakahany EE (2000). „M(2) and M(4) muscarinic receptor subtypes couple to activation of endothelial nitric oxide synthase.”. Pharmacology 61 (1): 37–42. DOI:10.1159/000028378. PMID 10895079.
Obara K, Arai K, Miyajima N, et al. (2000). „Expression of m2 muscarinic acetylcholine receptor mRNA in primary culture of human prostate stromal cells.”. Urol. Res. 28 (3): 196–200. DOI:10.1007/s002400000113. PMID 10929429.
Rang, H. P. (2003). Pharmacology. Edinburgh: Churchill Livingstone. ISBN 0-443-07145-4.
Boron, W. F and Boulpaep, E. L. (2005). Medical Physiology. Philadelphia: Elsevier Saunders. str. 387. ISBN 1-4160-2328-3.

Spoljašnje veze

„Acetylcholine receptors (muscarinic): M₂”. IUPHAR Database of Receptors and Ion Channels. International Union of Basic and Clinical Pharmacology. Arhivirano iz originala na datum 2015-01-02.
MeSH CHRM2+protein,+human

[1] Gosso MF, van Belzen M, de Geus EJ, et al. (2006). „Association between the CHRM2 gene and intelligence in a sample of 304 Dutch families”. Genes, Brain and Behavior 5 (8 pages=577–584). DOI:10.1111/j.1601-183X.2006.00211.x. PMID 17081262.

[2] Dick DM, Aliev F, Kramer J, et al. (2007). „Association of CHRM2 with IQ: converging evidence for a gene influencing intelligence”. Behav. Genet. 37 (2): 265–272. DOI:10.1007/s10519-006-9131-2. PMID 17160701.

[3] Lind PA, Luciano M, Horan MA, et al. (September 2009). „No association between Cholinergic Muscarinic Receptor 2 (CHRM2) genetic variation and cognitive abilities in three independent samples”. Behav. Genet. 39 (5): 513–23. DOI:10.1007/s10519-009-9274-z. PMID 19418213.

[Rang-4] Rang, H. P. (2003). Pharmacology. Edinburgh: Churchill Livingstone. ISBN 0-443-07145-4.

[Boron-5] Boron, W. F and Boulpaep, E. L. (2005). Medical Physiology. Philadelphia: Elsevier Saunders. str. 387. ISBN 1-4160-2328-3.

[entrez-6] 6,0 ^6,1 „Entrez Gene: CHRM2 cholinergic receptor, muscarinic 2”.

[pmid16539379-7] Scapecchi S, Matucci R, Bellucci C, Buccioni M, Dei S, Guandalini L, Martelli C, Manetti D, Martini E, Marucci G, Nesi M, Romanelli MN, Teodori E, Gualtieri F (March 2006). „Highly chiral muscarinic ligands: the discovery of (2S,2'R,3'S,5'R)-1-methyl-2-(2-methyl-1,3-oxathiolan-5-yl)pyrrolidine 3-sulfoxide methyl iodide, a potent, functionally selective, M2 partial agonist”. J. Med. Chem. 49 (6): 1925–31. DOI:10.1021/jm0510878. PMID 16539379.

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